184 million Americans are overweight and 47 million of these have the metabolic syndrome, a cluster of type 2 diabetes, heart disease, liver disease, blood vessel disease, etc. Specific Aim 1 tests the novel hypothesis that they result from impaired partitioning of the surplus lipids that caused obesity. When rats with congenital leptin resistance develop obesity and metabolic syndrome, their organs become overloaded with lipotoxic derivatives of fatty acids (FA), which normally are confined to fat cells. In leptin-responsive rats obesity-induced hyperleptinemia protects nonadipose tissues from ectopic lipid deposition by partitioning surplus calories into the adipocyte storage space through hypothalamic actions that limit the intake of surplus calories and through direct stimulation of oxidation of unutilized FA in nonadipose tissues. Lack of leptin action causes ectopic lipid deposition, functional impairment of the affected tissues (lipotoxicity), and increased lipid-induced apoptosis. The resulting organ failure is clinically identical to the metabolic syndrome. While the best treatment for metabolic syndrome is the intake of calories not exceeding caloric expenditure, new pharmacologic strategies for preventing and reversing this modern plague are emerging. Specific Aim 2 has equally far-reaching public health implications. We have observed that leptinized islets can survive without immuno suppression and function for at least a year when transplanted into insulin-deficient ketoacidotic diabetic rats, whereas unleptinized islets lose all function within 3 weeks. How lipid-lowering protects normal cells against lethal environmental insults is of enormous potential interest in clinical medicine. Elucidation of the mechanism of their year-long survival for a year may not only advance "cure" of Type 1 diabetes and other disorders treated by organ transplantation, but may lead to novel protective weapons against other cytodestructive clinical disorders. The fatty acid (FA) levels in organs may influence their ability to survive various types of injury. Our lab has shown that leptin, an adipocyte hormone, prevents high FA levels in organs by partitioning the excess caused by overeating into fat cells when caloric intake is excessive. When partitioning is impaired, FA spillover causes metabolic syndrome. We also find that by lowering FA, we can make cells resistant to various noxious events. FA-depletion of pancreatic islet transplants makes them resistant to rejection. Using FA-depleted islets we have been able to "cure" insulin-deficient diabetes in rats for ~1 year without immunosuppression. [unreadable] [unreadable] [unreadable]